Cocaine use among women of childbearing age is alarmingly high and renders a sizable population of children at risk for the long-lasting neurobehavioral abnormalities associated with prenatal cocaine exposure, such as difficulty modulating attention, impulsivity, responsivity, and deficits in short-term memory. While these clinical studies demonstrate harmful effects of prenatal cocaine, controlled studies in laboratory animals are needed to understand more fully the effect that gestational cocaine exposure has on the brain biochemistry of the offspring. Our progress strongly supports our original hypothesis that prenatal cocaine disrupts function in the mesoprefrontal system, namely the medial prefrontal cortex and A10 DA neurons that project there, and that this deficit would be most apparent under mildly stressful conditions. Specifically, in prenatal cocaine rats, we have observed 1) enhanced activation of both the A10 neurons and the intrinsic neurons of the prefrontal cortex, as indicated by expression of the immediate-early gene, Fos, 2) ventromedial prefrontal cortex dopamine turnover and serum corticosterone levels to be hyper-responsive to mild stress, 3) a 25% loss of A10, but not A8 or A9, neurons, likely the result of gestational changes precipitated by cocaine, and 5) poor short-term memory. We now propose to pursue these intriguing results by investigating 3 interrelated aspects of the hyper-reactive mesoprefrontal system, specifically, 1) the mechanism of the altered dopaminergic response to stress in the prefrontal cortex, possibly linked to enhanced excitatory input, 2) the consequences of the 25% loss of A10 neurons including potential changes in innervation and reactivity of prefrontal dopamine neurons, and 3) the hyper-reactive Fos expression in either or both the excitatory pyramidal and inhibitory interneurons of the prefrontal cortex and the relationship to cognitive deficits. These studies will utilize our expertise in catecholamine biochemistry together with recent progress made in our laboratory including development of an intravenous, prenatal cocaine model, use of a predator odor stress (TMT), use of a short-term memory task free of reference memory components, rewards or punishments, and, finally, stereological techniques for microscopy studies. We anticipate that these studies will provide valuable scientific insights into the biochemical underpinnings of the mesoprefrontal system dysfunction induced by prenatal cocaine exposure, advance our understanding of the neurobiology of the deficits, and, ultimately, permit the logical treatment of the deficits induced in exposed children